PHCP 403 by L. K. Sarki

PHCP 403 by L. K. Sarki

objectives To gain insight into the epidemiology of HIV To gain basic understanding of the etiology of HIV disease To know the clinical manifestations of the disease To gain a basic understanding of the treatment of HIV disease To be aware of the complexities of treatment

What does it stand for? HIV Human Immunodeficiency Virus Causes a gradual decline in immune function by destroying CD4 immune helper cells AIDS Acquired Immunodeficiency Syndrome Diagnosed when the patient suffers one a list of AIDS defining illness

First reports: MMWR 1981 MMWR report on pneumocystis pneumonia in live previously healthy young men in Los Angeles-June 5 1981 Kaposis s and pneumocystis pneumonia among homosexual men-new York and California

Early history of AIDS July 81: Jan 82: July 82: Dec 82: Infections noted in haemophiliacs, Haitians Syndrome termed GRID CDC defines AIDS 4 cases of unexplained immune deficiency in infants reported (MMWR)

Early history of AIDS Jan 83: May 83: April 84: Aug 84: May 86: First screening of high risk blood donors Pasteur institute report lymphadenopathy virus (LAV) Discovery of AIDS virus (HTLV-III) by Robert Gallo announced in USA First commercial AIDS test Virus remained HIV

Evolving therapy management 1981-87: Treatment of opportunistic diseases and symptoms only 1987: First antiretroviral (ZDV) licensed 1991-92: Availability of other NRTIs (ddi) 1994-95: Dual combination therapy (2 NRTIs) 1995: Quantification of HIV load by PCR

Evolving therapy management 1995: First HIV protease inhibitor and introduction of HAART 1996: Non-nucleoside RT inhibitors (NNRTIs) 1998: Realization of the difficulty (impossibility?) of eradicating HIV 1998: Resistance testing 2000: PI boosting 2001: Therapeutic drug monitoring

Global summary of the AIDS epidemic 2013 Number of people Total living with HIV in 2013 Adults Women Children (<15 years) People newly infected with HIV in 2013 Total Adults Children (<15 years) 35.0 million [33.1 million 37.2 million] 31.8 million [30.1 million 33.7 million] 16.0 million [15.2 million 16.9 million] 3.2 million [2.9 million 3.5 million] 2.1 million [1.9 million 2.4 million] 1.9 million [1.7 million 2.1 million] 240 000 [210 000 280 000] AIDS deaths in 2013 Total Adults Children (<15 years) 1.5 million [1.4 million 1.7 million] 1.3 million [1.2 million 1.5 million] 190 000 [170 000 220 000]

Adults and children estimated to be living with HIV 2013 North America and Western and Central Europe 2.3 million Caribbean 250 000 [230 000 280 000] [2.0 million 3.0 million] Latin America 1.6 million [1.4 million 2.1 million] Middle East & North Africa 230 000 [160 000 330 000] Sub-Saharan Africa 24.7 million [23.5 million 26.1 million] Eastern Europe & Central Asia 1.1 million [980 000 1.3 million] Asia and the Pacific 4.8 million [4.1 million 5.5 million] Total: 35.0 million [33.2 million 37.2 million]

Estimated number of adults and children newly infected with HIV 2013 North America and Western and Central Europe 88 000 [44 000 160 000] Caribbean 12 000 [9400 14 000] Latin America 94 000 [71 000 170 000] Middle East & North Africa 25 000 [14 000 41 000] Sub-Saharan Africa 1.5 million [1.3 million 1.6 million] Eastern Europe & Central Asia 110 000 [86 000 130 000] Asia and the Pacific 350 000 [250 000 510 000] Total: 2.1 million [1.9 million 2.4 million]

Estimated adult and child deaths from AIDS 2013 North America and Western and Central Europe 27 000 [23 000 34 000] Caribbean 11 000 [8300 14 000] Latin America 47 000 [39 000 75 000] Middle East & North Africa 15 000 [10 000 21 000] Sub-Saharan Africa 1.1 million [1.0 million 1.3 million] Eastern Europe & Central Asia 53 000 [43 000 69 000] Asia and the Pacific 250 000 [210 000 290 000] Total: 1.5 million [1.4 million 1.7 million]

About 6 000 new HIV infections a day in 2013 About 68% are in Sub Saharan Africa About 700 are in children under 15 years of age About 5 200 are in adults aged 15 years and older, of whom: almost 47% are among women about 33% are among young people (15-24)

Epidemiology of HIV in Nigeria: Key Facts 2008 2012 National Median HIV Prevalence 4.6% 4.1% Estimated Number of PLWHIV 2,980,000 3,459,363 Annual AIDS Death 192,000 217,148 Number requiring Antiretroviral Therapy 857,455 1,449,166 New HIV Infections 336,379 388,864 Total Number of AIDS Orphans 2,175,760 2,193,745

Transmission Infection can be acquired through 4 main routes Unprotected sexual intercourse (vaginal or anal) About 85% of all infections Sharing needles Injectable drug use Needlesticks from HIV infected patients» Usually healthcare workers Transfusions Vertical transmission from mother to child Prenatal infection breastfeeding

pathogenesis CD4 is a receptor on the white blood cells HIV uses (binds) the CD4 receptor to infect cells Once bound to the CD4 Coreceptors CCR-5 CXCR-4 Are required for fusion

pathogenesis HIV fuses with the cell releasing its single-stranded RNA in addition to other specific enzymes into the host cell Single-stranded viral RNA is then transcribed by reverse transcriptase into a double-stranded proviral DNA Proviral DNA is then incoporated into the host cell s genetic material through the integrase enzyme

pathogenesis HIV then uses the infected host cell s machinery to translate, transcribe and produce immature virions made infectious with the help protease enzymes bud and break from the host cell Mature virion becomes free to infect new host cells and subsequently produce more infectious virus

pathogenesis Destruction of the existing and inhibition of the formation of new CD4 cells Transient depletion of CD4 cells occurs Places the host at an increased risk for opportunistic infections Initially, patients may complain of nonspecific symptoms acute retroviral syndrome Fever, lymphadenopathy, fatigue and night sweats

CD4 count CD4 count used as a marker of immune function The lower the CD4 the less efficient the immune system Low CD4 (<200 cells/mm 3 ) puts patients at risk of opportunistic infections

Clinical manifestations Opportunistic infections Rare in otherwise healthy immunocompetent individuals due to intact cell-mediated immunity against infections Immunosuppresed individuals HIV Shingle (herpes zoster) Oral thrush Anaemia, weight loss Recurrent candidal vaginal infections Active tuberculosis

Clinical manifestations In more advanced cases- CD4 <200cells/mm 3 Tuberculosis Oesophageal candida Pneumocyctis jiroveci pneumonia Toxoplasmosis Kaposi s sarcoma Cryptococcal meningitis Severely depressed immune system CD4 75 cells/mm 3 Dessiminated CMV

Testing for HIV ELISA based test- antibody based test Highly sensitive & specific Represent a good screening test But 3 months window till positive Same day testing now available Walk in clinic Finger prick test Result available in 10 to 15 minutes

Viral load (VL) The amount of virus in 1 millilitre of blood Without treatment VL from 5000 5 million copies/ml Aim of treatment to become undetectable (VL <50 cps/ml) An undetectable VL reduces amount of replication of virus, and reduces chance of resistance to antiretroviral drugs

When to treat HIV disease stage CD4 count(cells/mm 3 ) Recommendation Early (primary) infection Any CD4 level Treatment in clinical trial; or neurological involvement; AIDS-defining illness; or CD4 <200cells/mm 3 >3/12 Established (chronic) infection without symptoms CD4 >500 CD4 351 500 CD4 201 350 CD4 < 200 Consider enrolment into when to start trial Treat in specific situations with higher risk of clinical events AIDS diagnosis (except TB); HBV; HCV; CVD Treat ASAP when patient ready Start treatment Established (chronic) infection with symptoms Any CD4 count Start treatment (except for TB when CD4 >350cells/mm 3 ) pregnancy Any CD4 count Use hospital/national/international pregnancy guidelines HIV- associated nephropathy (HIVAN) Any CD4 count Start but consider renal elimination of ARVs, in particular NRTIs

Available ARVs NRTIs: Abacavir Didanosine Emtricitabin e Lamivudine Stavudine Tenoforvir Zidovudine NNRTIs Efavirenz Nevirapine Etravirine Protease inhibitors: Atazanavir Darunavir Amprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir New Classes Fusion inhibition: Enfuvirtide R5 inhibitors: Maraviroc Integrase inhibitors: Raltegravir

Highly active antiretroviral therapy (HAART) Most evidence for: 2 NRTIs + NNRTI (regimen of choice) Alternatively 2 NRTIs + boosted PI

What to treat with Drug 1 Drug 2 Drug 3 Preferred: Tenoforvir ع : or و Abacavir Alternative: zidovudine لا : or Didanosin لا,و Lamivudine Or ع emtricitabin Preferred: ع Efavirenz Alternative kaletra others Specific groups ق Nevirapine Tenoforvirع and Emtricitabin available as the co-formulated Truvada and in combination with efavirenz as Atripla Abacavir and Lamivudine available as the co-formulated Kivexa و Zidovudine and Lamivudine available as the co-formulated Combivir لا Nevirapine should be avoided in women with CD4 >250 cells/mm3 and males with CD4 ق >400cells/mm3 due to significantly increased risk of hepatitis and severe rash

Adherence affects clinical outcome 95% adherence is required to achieve undetectable viral load Reasons for poor adherence include: Side effects Disclosure Stigma Too complicated Reminder of illness Don t remember

toxicities Zidovudine Anaemia (esp with combivir as AZT 300mg bd) Tenoforvir Concerns over renal safety Nevirapine Hepatotoxicity Remember CD4 cut off for Rx rash

toxicities Abacavir Hypersensitivity in 5 7% of patients Characterised as rash, or 2 of the following: Fever Shortness of breath, or sore throat or cough Nausea, vomiting, diarrhoea or abdominal pain Severe tiredness or achiness, or generally ill feeling NB: genet link: HLAB*5701

toxicities Efavirenz CNS disturbances (concern if Hx of depression) Not advised if considering pregnancy Preferred NNRTI

atripla Tenoforvir 300mg Emtricitabine 200mg Efavirenz 600mg One pill once a day

Cytochrome P450 Induction/inhibition of CYP3A4 can influence drug metabolism NNRTI/rifampicin induce CYP3A4 Ritonavir inhibits CYP3A4 Retonavir used as PK booster for other PIs

statins Drug (metabolism) NNRTI PI (boosted) Simvastatin (CYP3A4, 2D6, 2C9) Fluvastatin (CYP2C9>>3A4) Atorvastatin (CYP3A4) 60% AUC simva Advice: avoid!!! No sig. interaction Rx as normal 40% atorva levels. Start at 20mg and titrate 600 2000x AUC simva Advice: avoid!!! No sig. interaction Rx as normal but may see more s/e at max dose 4 6x atorva levels. Advice: start with 10mg od and titrate. Usual max 20mg od.others? Check an don t assume

Anti epileptics Drug (metabolism) NNRTI PI (boosted) Phenytoin (CYP2C9) Carbamazepine (CYP3A4) 30% in both phenytoin and NNRTI levels. Advice: AVOID for chronic care carb levels NNRTI levels Advice: AVOID 30% in both phenytoin and PI levels. Advice: AVOID for chronic care 50% carb levels & PI levels. Advice: AVOID.Others? Check an don t assume

HIV & pregnancy Not a contraindication and not discouraged National antenatal screening Actions: Initiate HAART 20-28 weeks C-section if VL >50cps/ml Neonate given 4/52 PEP Bottle feed (not breast feeding)

Prophylaxis? Post-exposure prophylaxis (PEP) is short-term antiretroviral treatment to reduce the likelihood of HIV infection after potential exposure, either occupationally or through sexual intercourse 28 day course ART Vaccine?